July 2024 - Medical Devices Regulatory Insights

MHRA announces a proposed framework for international recognition of medical devices

The Medicines and Healthcare products Regulatory Agency (MHRA) on 21 May 2024 published a statement of policy intent for international recognition of medical devices.

The MHRA’s statement of policy intent describes how the UK Government intends to recognise regulatory approvals from Australia, Canada, the European Union and the United States of America depending on device type, class, and prior approval. The MHRA continues to review
the list of comparable regulator countries and is in active discussions with the Pharmaceuticals and Medical Devices Agency (PMDA) to explore the recognition of medical device approvals from Japan.

The proposed framework is still in draft, and the final version would be integral with the future core regulations.

Original source: GOV.UK. Published: 21 May 2024.

Implementation of the future regulations

The UK government intends to introduce new regulations for medical devices that prioritise patient safety and give patients access to the medical devices they need. The regulations will be delivered through four statutory instruments. It is intended that priority measures to enhance post-market surveillance will be put in place first in 2024, with core elements of the new framework expected to be in place in 2025.

Transitional arrangements

The government has put in place legislation that amends The Medical Device Regulations 2002 (SI 2002 No 618, as amended) (UK MDR) to extend the acceptance of CE marked medical devices on the Great Britain market. The transition timelines can be found here.

General medical devices compliant with the EU medical devices directive (EU MDD) or EU active implantable medical devices directive (EU AIMDD) with a valid declaration and CE marking can be placed on the Great Britain market up until the sooner of expiry of certificate or 30 June 2028
In vitro diagnostic medical devices (IVDs) compliant with the EU in vitro diagnostic medical devices directive (EU IVDD) can be placed on the Great Britain market up until the sooner of expiry of certificate or 30 June 2030

MHRA is reviewing its position on acceptance of EU MDR and EU IVDR CE certificates renewed after a strengthened future regime for medical devices is in place, taking on board stakeholder feedback and will publish an update on this in due course. The existing legislation does not prevent reliance on renewed EU MDR and EU IVDR certificates for placing medical devices on the GB market until 30 June 2030.

The future core regulations will:

introduce several improvements for implantable medical devices; up-classifying them which will result in more stringent pre- and post-market requirements and requiring manufacturers to provide implant cards to enable patients to know which device they have had implanted
ensure devices have a unique device identifier (UDI)
change the classification of several types of devices, specifically increasing the class of certain software as a medical device and aligning IVD classifications with those of the International Medical Device Regulators Forum
strengthen the requirements for quality management systems and technical documentation
introduce a framework for international recognition, enabling swifter access for devices already approved by comparable regulators as well as for those who have Medical Device Single Audit Program (MDSAP) certificates
include new requirements for exempt in-house manufactured devices and custom-made devices
include new requirements for the claims manufacturers can make about their medical
devices requiring them to align with their statement of intended purpose
include new requirements for clinical investigations
for essential requirements for medical devices being placed on the market in GB, bring in a consistent approach with that of the EU (this will include cybersecurity requirements for software as a medical device including for artificial intelligence)
clarify the requirements for conformity assessments and approved bodies
clarify the requirements for economic operators; manufacturers, importers and distributors, and introduce a requirement to have a person qualified in regulatory compliance

Original source: GOV.UK. Published: 21 May 2024.

MHRA’s Public Consultation on Common Specifications for High-Risk IVDs

On 21 May 2024, the Medicines and Healthcare products Regulatory Agency (MHRA) announced the launch of a four-week public consultation seeking the views of various stakeholders to improve safety measures for high-risk IVDs by including Common Specification (CS)
requirements in the UK legislation (Medical Devices Regulations 2002 (MDR 2002)). In addition, they also seek views on the removal of the Coronavirus (SARS-CoV-2) Test Device Approval (CTDA) process (desktop review) to avoid duplication with the CS requirements.

Original source: Emergo by UL. Published: 24 May 2024

MDCG aims to harmonize adverse events reports for surgical mesh in the EU

The Medical Device Coordination Group (MDCG) wants to harmonize adverse events reporting for surgical mesh implants across EU member states. Over the past decade, there have been reports of adverse events associated with the use of surgical mesh to treat pelvic organ prolapse and stress urinary incontinence, which in some cases have led to serious injury or death.

On June 11, MDCG published a Device Specific Vigilance Guidance (DSVG) on harmonized reporting to Competent Authorities (CA) for urogynaecological surgical mesh implants to treat pelvic organ prolapse and stress urinary incontinence. It details how manufacturers should report adverse events associated with the products to comply with the EU Medical Device Regulation (MDR) and emphasizes that the guidance does not replace or extend any of the vigilance reporting requirements already outlined in the MDR.

“It is the manufacturer’s responsibility to judge each event on its own merit and to ensure compliance with the statutory reporting requirements contained within the MDR,” said MDCG.

The guidance provides an overview of handling different reports, including individual serious incidents, periodic summary reports, and trend reports. It references circumstances when the different types of reports are warranted under MDR and how they should be presented. For instance, manufacturers are expected to send individual serious reports to CAs even in cases where there is ambiguity over whether the issue is reportable or when they may need more time to clarify the incident’s root cause. On the other hand, manufacturers can agree to file periodic summary reports with their respective CAs.

“This is possible when similar serious incidents involving the same specific device or device type occur and for which the root cause has been identified or a field safety corrective action has been implemented or where the serious incidents are common and well documented,” said MDCG. “The format, content and frequency of periodic summary reports should be agreed with the Coordinating Competent Authority (in consultation with the Competent Authorities participating in the Periodic Summary Reporting).”

The group also said that periodic summary reports should follow its guidance on harmonized administrative practices and alternative technical solutions until the European database on medical devices (EUDAMED) is fully operational.

The guidance states that manufacturers are responsible for keeping an eye out for any statistically significant increases in the frequency or severity of incidences that could affect the product’s risk-benefit profile and reporting them to their respective CAs.

“Clinical references or current clinical guidelines for Urogynaecological Surgical Mesh Implants used for Pelvic Organ Prolapse repair and Stress Urinary Incontinence may be used by manufacturers in order to identify incident examples and complications,” the guidance states. “Urogynaecological Surgical Mesh Implants used for Pelvic Organ Prolapse repair and Stress Urinary Incontinence manufacturers may refer to relevant local clinical guidelines when identifying incident examples and complications.”

It also includes several examples of how the different reports should be filed and a link to terminologies used by the International Medical Device Regulators Forum (IMDRF) that can be used when reporting adverse events.

Original source: RAPS. Published: 13 June 2024

Second Report on the European Clinical Evaluation Consultation Procedure (CECP)

The European Commission (EC) published its second annual overview concerning medical devices subject to the Clinical Evaluation Consultation Procedure (CECP) (Article 54) of the Medical Devices Regulation (MDR) (EU) 2017/745. This is an update to the first CECP report (April
2021-June 2022). The current report summarizes activities of expert panels to the CECP from July 2022 through June 2023.

CECP and Notified Body requirements

The Notified Bodies (NBs) review the manufacturer’s clinical evidence and generate the clinical evaluation assessment report (CEAR, MDCG 2020-13). NBs are required to follow the CECP when performing a conformity assessment of Class III implantable devices as well as Class IIb active devices intended to administer and/or remove a medicinal product (such Class IIb devices are referred to as “ARMP devices” in the report).

Unless otherwise exempted by Article 54(2), the CECP is intended to provide “independent scientific opinions by expert panels” based on the NB’s CEAR. Note that MDCG 2019-3 provides guidance on CECP exemptions per Article 54(2)(b).

MDR Article 54 reporting rules

These annual overviews address the EC’s obligation(Article 54(4)) to provide annual reporting on devices subject to the CECP (references to the second report):

NB CECP applications and whether the CECP applies (Annex I) or devices exempted from the CECP (Table 2, Annex 2)
Devices that require the CECP and whether the expert panel provided a scientific opinion (Table 1, Table 3) and
Devices from the group above, for which the NB did not adhere to the expert panel counsel (section 4)

Devices are identified by EMDN type with synopsis shared per category.

CECP second report findings

Thirteen NBs submitted 353 devices as deemed within the CECP scope, the NB involved determined that 36 (10.1%) of the devices were not exempted from the CECP.

The majority of the 36 devices were Class III implantable devices (34, 94.4%) whereas two were Class IIb ARMP devices (5.6%).

Of the 36 devices, the expert panels decided to provide an opinion on four of 35 (12%) applications received, with one application pending.

The remaining 317 devices consisted of 285 (89.9%) Class III implantable devices and 32 (10.1%) Class IIb ARMP devices. The most common reason for exemption (314, 99.1%) was the modification of a device already marketed by the same manufacturer for the same intended purpose and the modifications not adversely affecting the benefit-risk ratio.

Scientific opinions from the expert panels to the CECP are posted on the EC website. The opinions are organized by the expert panels, the titles provide the date the dossier was submitted as well as the four-digit number of the NB involved.

Original source: Emergo by UL. Published: 16 April 2024.

MDCG guidance tries to reduce burden of bringing orphan devices to EU market

Manufacturers developing orphan medical devices in the EU should be given extra leeway to bring their products to market, especially considering the higher evidence threshold set by the Medical Device Regulations (MDR), according to a new guidance from the Medical Device Coordination Group (MDCG). The group also emphasized that manufacturers may need to rely more on post market studies and non-clinical data to support such products.

On 25 June, MDCG published guidance for manufacturers and notified bodies detailing considerations for defining an orphan device and the potentially limited evidence needed
to determine whether it has proven to be safe and effective.

“The level of clinical evidence that is required to place medical devices on the market has been increased by the MDR, including an increased need for pre-market clinical investigations for certain higher risk devices to verify their safety and clinical performance,” said MDCG. “These increased clinical evidence requirements present a challenge for devices specifically intended for use in rare diseases/conditions, or in specific indications for rare cohorts of patients with an otherwise non-rare disease/condition.”

“The increased, and at times unpredictable, financial costs associated with compliance with MDR requirements, including MDR certification, can make it prohibitive for manufacturers to place orphan devices on the EU market, as the low volumes of sales may not offset the financial costs,” the group added. The guidance notes that some manufacturers may develop devices with both orphan and non-orphan indications, which may be challenging to prove safe and effective in a smaller population. In such situations, the MDCG emphasized that the guidance only applies to the orphan indication and can’t be used to leverage authorization for the more general indication.

The guidance states that applying MDR requirements to orphan devices should be balanced and proportionate so that they don’t unduly prevent such products from coming to market.

To qualify as an orphan device, the manufacturer should provide evidence that the intended indication it treats is limited to conditions that afflict at most 12,000 people in the EU every year.

The guidance also states that the manufacturer can justify their product as an orphan device if it afflicts a subpopulation where a disease affects at most 12,000 people annually, even if the broader disease indication affects more than 12,000 people annually.

“In cases where the device is intended to treat, diagnose, or prevent a rare disease as defined in the EU and affecting no more than 5 in 10,000 persons in the EU, and where the device is expected to be used in not more than 12,000 such individuals per year, this can be accepted as sufficient justification of the epidemiological part of the criteria,” the guidance added.

MDCG said that it may be challenging for manufacturers to generate sufficient clinical trial data in the premarket setting, considering the difficulty of enrolling enough subjects. With that in mind, orphan devices may be allowed on the market based on limited premarket data, but manufacturers must take appropriate measures such as agree to conduct post-market clinical follow-up (PMCF) studies.

“There must be sufficient clinical evidence to demonstrate an expected clinical benefit and that the device performs as intended with an acceptable level of safety,” said MDCG. “To address and resolve any limitations in pre-market clinical evidence as soon as possible, an adequate PMCF plan must be developed to ensure appropriate collection and generation of post-market clinical data.”

Non-clinical data may also play a key role in allowing orphan devices on the market, especially when it is difficult to generate clinical trial data said MDCG. The group added that all sources of non-clinical data should be considered when developing orphan devices.

“If the non-clinical data provide substantial high-quality evidence to support the safety and performance of the orphan device and its expected clinical benefit, this can reduce the burden of required pre-market clinical data and can help to justify CE marking with limitations in clinical data that can be met through PMCF activities,” the guidance added.

Besides providing recommendations on developing evidence to justify bringing an orphan device to market, the guidance also includes details on how manufacturers and notified bodies can get advice from European Medicines Agency (EMA) expert panels to help their product development.

Original source: RAPS. Published: 25 June 2024

Guidance Documents Issues By the Medical Device Coordination Group (MDCG)

April 2024

MDCG 2024-4: Safety reporting in performance studies of in vitro diagnostic medical devices under Regulation (EU) 2017/746
MDCG 2024-4 Appendix: Appendix – Performance Study Summary Safety Reporting Form
MDCG 2024-5: Guidance on the Investigator’s Brochure content
MDCG 2024-5 Appendix A: Appendix A of the MDCG 2024-5
MDCG 2022-9 rev.1: Summary of safety and performance template

May 2024

MDCG 2024-6: Preliminary re-assessment review (PRAR) form template (MDR)
MDCG 2024-7: Preliminary assessment review (PAR) form template (MDR)
MDCG 2024-8: Preliminary assessment review (PAR) form template (IVDR)
MDCG 2024-9: Preliminary re-assessment review (PRAR) form template (IVDR)
MDCG 2022-4 rev.2: Guidance on appropriate surveillance regarding the transitional provisions under Article 120 of the MDR with regard to devices covered by certificates according to the MDD or the AIMDD

June 2024:

MDCG 2024-10: Clinical evaluation of orphan medical devices
MDCG 2024-1-5: DSVG 05 on Urogynaecological Surgical Mesh Implants used for Pelvic Organ Prolapse repair and Stress Urinary Incontinence
SCHEER guidelines: Update on the guidelines on the benefit-risk assessment of the presence of phthalates in certain medical devices covering phthalates which are carcinogenic, mutagenic, toxic to reproduction (CMR) or have endocrine-disrupting (ED) properties
MDCG 2022-13 Rev.1: Designation, re-assessment and notification of conformity assessment bodies and notified bodies.

New ISO Standard Released

ISO 17665:2024(en): Sterilization of health care products – Moist heat – Requirements for the development, validation and routine control of a sterilization process for medical devices

US FDA, Health Canada and UK MHRA Update on Transparency Guiding Principles for Machine Learning-Enabled Medical Devices

The US Food and Drug Administration (FDA), Health Canada and UK MHRA (June 13) built on their 2021 guiding principles for good machine learning practice for medical device development by further identifying guiding principles for transparency for machine learning-enabled medical devices (MLMDs).

Additional guidance on ML medical devices

These principles build upon principles 7 and 9 of the initial guiding principles:

Principle 7: Focus is placed on the performance of the human-AI team
Principle 9: Users are provided with clear, essential information

The principles emphasize a human-centered design (HCD), ISO 9241-210:2019 Ergonomics of human-system interaction – Part 210: Human-centered design for interactive systems, an “approach to systems design and development that aims to make interactive systems more usable by focusing on the use of the system and applying human factors/ergonomics and usability knowledge and techniques”.

Guiding principles

Because MLMDs can require the user and other stakeholders in the healthcare ecosystem to understand complex information that is often context-dependent, information must be provided that allows the user to identify and evaluate the risk and benefits associated with the device. Information should be provided with the intent of enhancing the audiences’ understanding of the device, its intended use and how it fits into the clinical workflow. Additionally, information should be provided in simple terms demonstrating how the MLMD processes input information and reaches its output. This allows healthcare professionals and other stakeholders to critically assess this information, its validity and how it is utilized.

Guiding principles, risk management and clinically relevant information

The guiding principles also mention disclosing risk management activities and clinically relevant information to foster trust about the safety and effectiveness of the device. While it is already good practice to disclose clinically relevant information and residual risks, clarity is perhaps needed on the level of detail that must be included. Too much information, particularly on risk management activities which can be considerable and are executed continually through the device lifetime may lead to information overload and distract from critical information that needs to be conveyed to the user.

Impact

Transparency is a fundamental principle of good machine learning practice (GMLP) and plays a pivotal role in supporting the safety of ML-enabled medical devices. The continued collaboration between US FDA, Health Canada and UK MHRA paves the way for more formal regulation of these devices, as well as global adoption by other regulators. The guiding principles do more than support adequate medical device labelling. There is an emphasis on device design; usability, risk management, clinical information. These are principles that those in the medical device industry are familiar with but are worth mentioning in the context of MLMDs.

Original source: Emergo by UL. Published: 26 June 2024.

FDA Issues Overdue Draft Guidance on Clinical Trial Diversity Action Plans

The U.S. Food and Drug Administration (FDA) released its long-awaited draft guidance on Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies. This draft guidance replaces the agency’s similarly-titled April 2022 draft guidance and has been issued to satisfy a requirement under the Food and Drug Omnibus Reform Act of 2022 (FDORA) that the agency update or issue new draft guidance on the format and content of Diversity Action Plans

FDA notes that, by statute, the requirements under FDORA for Diversity Action Plans apply to clinical studies with enrolment commencing after 180 days from publication of final guidance, giving industry and stakeholders time to review and comment on the FDA’s draft guidance and to begin adapting to the direction the FDA is moving with this draft guidance. The FDA also carves out the following from needing a Diversity Action Plan:

(1) Clinical studies of drugs with protocols submitted within 180 days following the publication of the final guidance where enrolment is scheduled to begin 180 days after publication of the final guidance;
(2) Clinical studies of devices received by FDA in IDE applications within 180 days after publication of the final guidance; and
(3) Clinical studies of devices that do not require an IDE application to be submitted to FDA that are approved by an institutional review board (IRB) or independent ethics committee (IEC) within 180 days after the date of publication of the final guidance.

In setting enrollment goals, FDA points out that sponsors should take into account the overall clinical development strategy—i.e., if there are multiple clinical studies that would be subject to Diversity Action Plan requirements, the sponsor should work towards “overall proportionate
representation,” even if an individual study does not have proportionate representation.

Finally, the draft guidance specifies timelines for submitting these plans and procedures for receiving feedback from the FDA. Additionally, the document discusses waivers for these plans and encourages sponsors to consider publicly posting key information from their plans to promote transparency. The draft guidance is published in the Federal Register and will be open for 90 days for public comments.

Original source: GOODWIN. Published: 27 June 2024.

U.S. FDA Final Rule Published on Laboratory Developed Tests (LDTs)

Laboratory Developed Tests (LDTs) are IVDs that are designed, manufactured and used within a single clinical laboratory.

In September 2023, the FDA announced its intent (proposed rule) to regulate LDTs: LDTs would now require premarket authorizations analogous to IVDs.

At the end of January, the FDA shared the intended proposal to reclassify most IVDs currently classified as Class III to Class II devices.

On April 29, the FDA released the text of the Final Rule for LTDs. It was officially published May 6. The requirements will be phased in over the next four years.

Stage 1 (May 6, 2025): Complaint management and adverse event, correction and removal of reporting requirements
Stage 2 (May 6, 2026): Establishment registration and device listing, labeling, investigational use requirements
Stage 3 (May 6, 2027): Complete compliance to 21 CFR 820 (Note Quality Management System Regulation (QMSR) ISO 13485 incorporated effective February 2, 2026)
Stage 3.5 (November 6, 2027): LDTs subject to PMA, de novo and CBER licensing must be submitted
Stage 4 (May 6, 2028): LDTs subject to 510(k)s must be submitted

Original source: Emergo by UL. Published: 6 May 2024.

References
Image 1: IQVIA
Image 2: Pharmtech
Image 3: Europa commission
Image 4: RAPS
Image 5: MedtechIntelligence